By Akia Thorpe -

September 11, 2018

The US Food and Drug Administration (FDA) has published a draft guidance, Postapproval Changes to Drug Substances which discusses how the risk of one or more changes to a drug-substance manufacturing process during the drug-product application postapproval period should be assessed.

The draft guidance is applicable to holders of approved new drug applications, abbreviated new drug applications (ANDAs), new animal-drug applications, abbreviated new animal-drug applications, and holders of drug master files and veterinary master files.

"We know that post-market changes to manufacturing can reduce the possibility of a supply disruption due to quality problems, lower production costs and improve quality,” said FDA Commissioner Scott Gottlieb in a September 10, 2018 agency statement. “But it’s important that manufacturing changes be carefully evaluated to make sure that they don’t introduce the potential for adverse impacts on quality that might lead to new safety risks to the patient. For example, facility or equipment changes have the potential to change the physical properties of the drug substance, which can affect critical characteristics of the drug product, such as how it dissolves in the body.”

The draft guidance covers the following: facility, scale, and equipment changes associated with all steps of drug-substance manufacturing; specification changes to starting materials, raw materials, intermediates and the unfinished and final drug substance; synthetic manufacturing process changes; changes in the source of drug substance; and a change to the container-closure system of the drug substance. The guidance also provides recommendations regarding the documentation needed to support the changes for the drug substance or for the drug product made with a modified drug substance.

The FDA says it committed to issuing a guidance on postapproval changes to active pharmaceutical ingredient drug master files (DMFs), also known as Type II DMFs, and submission mechanisms for ANDA holders who reference these DMFs, as part of the reauthorization of the Generic Drug User Fee Amendments.